Psorospermin is a plant natural product that has demonstrated in vitro and in vivo activity against dmg resistant leukemia and lymphoma. We have previously demonstrated that this compound is a topoisomerase II poison, but is unique in that alkylation of DNA by psorospermin is a topoisomerase 11-mediated process. Because of the unique mechanism of action of this compound and insights into the molecular pharmacology and molecular biology of drug refractory leukemia and low-grade, mantle cell lymphoma, we have devised strategies to selectively target these cancers. The specific aims of this proposal are: 1. the synthesis of psorospermin and its analogues. 2. the biochemical and biological evaluation of psorospermin and a restricted set of analogues in in vitro and cell-free systems. 3. the evaluation of psorospermin analogues from a parallel synthesis program to down-regulate overexpressed oncogenes such as BCL-2 by site-directed alkylation using topoisomerase II. A variety of techniques, including solution and parallel synthesis, in vitro cytotoxicity assays, DNA chip array analysis, gel electrophoresis, promoter assays, and LM-PCR, will be used to carry out these objectives.